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M3 Muscarinic Receptor Knockout mice are hypophagic, lean, and have improved glucose tolerance and insulin sensitivity.

Acronym: Mutant Mouse: M3 Muscarinic receptor KO (Chrm3 tm1Jwe) Mouse NIDDK Contact: tao@niddk.nih.gov Principal Investigator(s): Hans Jurgen Wess

Description:

M3 Muscarinic Receptor Knockout mice are hypophagic, lean, and have improved glucose tolerance and insulin sensitivity.

The five Muscarinic Acetylcholine (ACh) receptors are G-protein coupled receptors (M1R-M5R). M1R, M3R and M5R selectively couple to Gq/G11; M2R and M4R selectively couple to Gi/Go.  M3 muscarinic ACh receptors are present in the central nervous system and the periphery.

M3R knockout mice are viable and fertile, and have no major morphological abnormalities.  They have a lean phenotype.  This results from a combination of reduced caloric intake and increased energy expenditure.  They eat less food than wild-type mice, possibly because a central cholinergic pathway that stimulates food intake is disrupted. They also expend more energy. Because of their lean phenotype, M3R knockout mice have improved glucose tolerance and increased insulin sensitivity.  Pharmacological blockade of central M3Rs may be a novel strategy for the treatment of obesity and associated metabolic disorders.

In the airway, vagally-mediated bronchoconstriction responses were abolished in M3R knockout mice in vivo, suggesting that M3R antagonists may be useful in the treatment of chronic obstructive pulmonary disease (COPD) and asthma.  Studies with M3R knockout mice also have shown that the M3R is the major muscarinic receptor mediating ACh-induced glandular secretion from exocrine and endocrine glands, including the secretion of insulin from pancreatic beta cells.

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